Hallucinogenic compounds, such as d-lysergic acid diethylamide (d-LSD) and mescaline, represent a structurally diverse group of psychoactive agents that produce a unique alteration in human consciousness and perception. Electrophysiological, biochemical and behavioral data suggest that hallucinogens interact with central serotonergic systems to produce their spectrum of effects. Recent radioligand binding data indicate that hallucinogens may interact with high and low affinity states of the 5-HT2 receptor (DOB and ketanserin binding sites). However, the functional correlates of the high and low affinity state of 5-HT2 receptors are not clear. Nor do we known their roles in the phenomena of tolerance and cross-tolerance of hallucinogen-induced physiological and behavioral effects. There have been no systematic studies performed examining the electrophysiological and biochemical processes underlying these phenomena. As a first step toward elucidating the mode of action of hallucinogens, we are to characterize the physiological and pharmacological properties of the 5-HT2 receptor in the rat medial prefrontal cortex (mPFc), an area with a high density of 5-HT2 receptors, using the techniques of single unit recording and microiontophoresis and micropressure injection techniques. Our preliminary results show that the actions of the phenylisopropylamine hallucinogens 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and 1- (2,5-dimethoxy-4-bromophenyl)-2-aminopropane (DOB) are mediated by 5-HT2 receptors. The hallucinogens DOI and DOB at a low ejecting current (0.5 nA) potentiate the excitatory action of 1-glutamate (GLU) on quiescent cells, but at higher currents, they dose-dependently suppressed spontaneously active and GLU-activated mPFc cells. It is possible that the facilitating and suppressant action of DOI and DOB is mediated by the high and low affinity state of 5-HT2 receptors, respectively. d-LSD, however, may act as a partial agonist for 5-HT2 receptors. In the present research application, we propose to characterize further and to study the pharmacological regulation of the high and low affinity state of 5-HT2 receptors (DOB and ketanserin binding sites), using a combinations of electrophysiological, biochemical (including phosphoinositide hydrolysis) and behavioral approaches. The action of various hallucinogens and non-hallucinogenic congeners of d-LSD and DOI on 5-HT2 sites will be systematically compared. The hypothesis that the reduced effectiveness of d-LSD on 5-HT2 sites may be the result of its interactions with alpha2 adrenergic and 5-HT1A sites will be systematically tested. Furthermore, the effect of systemic administration of specific hallucinogens at doses that produces behavioral tolerance on 5-HT2 receptors will be studied. The results of our proposed studies should help us to identify and understand 5-HT receptor subtypes involved in hallucinogen-induced effects, which, in turn, should help us to understand central serotonergic function.